ABSTRACT
Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). Small molecules exhibit more predictable pharmacokinetics than biologics, are less likely to induce immune responses, and can be administered orally. JAK inhibitors function by blocking the activity of JAK enzymes, which prevents the subsequent phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Nevertheless, JAK inhibitors can increase the risk of herpes zoster, cancer, major adverse cardiovascular events, and venous thromboembolism. S1PRMs bind to S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting the lymph nodes and migrating to the gut, thereby reducing inflammation and the immune response in the intestinal mucosa. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.
Subject(s)
Inflammatory Bowel Diseases , Janus Kinase Inhibitors , Sphingosine 1 Phosphate Receptor Modulators , Humans , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/pharmacology , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Sphingosine-1-Phosphate Receptors/metabolism , Sphingosine-1-Phosphate Receptors/antagonists & inhibitors , Receptors, Lysosphingolipid/metabolism , Receptors, Lysosphingolipid/antagonists & inhibitors , Crohn Disease/drug therapy , Indans , Oxadiazoles , Pyridines , TriazolesABSTRACT
BACKGROUND AND AIMS: Sphingosine 1-phosphate receptor modulators (S1PRMs) are an effective treatment for ulcerative colitis (UC). This review summarizes all available randomized trial data on the efficacy and safety of S1PRM therapy. METHODS: Multiple publication databases were systematically searched for randomized control trials (RCTs) of adults with moderate to severe UC treated with S1PRMs. Random effects meta-analysis was performed. The risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool, and the overall quality of evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We identified 7 RCTs (1737 patients) involving the use of S1PRMs for moderate to severe UC. During induction, S1PRM therapy was efficacious when compared with placebo for clinical remission [RR: 2.65 (95% CI: 2.00, 3.53)], clinical response [RR: 1.68 (95% CI: 1.48, 1.91)], endoscopic improvement [RR: 2.17 (95% CI: 1.76, 2.68)], endoscopic normalization [RR: 2.56 (95% CI: 1.58, 3.83)], mucosal healing [RR: 2.88 (95% CI: 1.94, 4.26)], and histologic remission [RR: 2.42 (95% CI: 1.60, 3.66)]. Similar results were seen throughout the maintenance peroid, although fewer data were available to pool; notably, both sustained [RR: 3.57 (95% CI: 1.23, 10.35)] and steroid-free [RR: 2.92 (95% CI: 1.35, 6.33)] remission were significantly increased by S1PRM. There were no significant differences in adverse events [RR: 1.02 (95% CI: 0.90, 1.15)] and infections [RR: 1.15 (95% CI: 0.82, 1.60)] between S1PRM and placebo. CONCLUSION: Pooling of RCT data confirms that S1PRM therapy is both effective and safe for patients with moderate to severe UC.
Subject(s)
Colitis, Ulcerative , Randomized Controlled Trials as Topic , Sphingosine 1 Phosphate Receptor Modulators , Humans , Colitis, Ulcerative/drug therapy , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/adverse effects , Treatment Outcome , Sphingosine-1-Phosphate Receptors , Severity of Illness Index , Remission InductionABSTRACT
So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35-55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.
Subject(s)
Azetidines , Benzyl Compounds , Brain-Derived Neurotrophic Factor , Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Female , Mice , Azetidines/pharmacology , Azetidines/therapeutic use , Benzyl Compounds/pharmacology , Benzyl Compounds/therapeutic use , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Mice, Inbred C57BL , Mice, Knockout , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Spinal Cord/metabolism , Spinal Cord/drug effects , Spinal Cord/pathologyABSTRACT
The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process.
Subject(s)
Gastrointestinal Microbiome , Inflammatory Bowel Diseases , Janus Kinase Inhibitors , Sphingosine 1 Phosphate Receptor Modulators , Humans , Gastrointestinal Microbiome/drug effects , Janus Kinase Inhibitors/pharmacology , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/microbiology , Inflammatory Bowel Diseases/metabolism , Pyrazoles/pharmacology , Colon/microbiology , Colon/metabolism , Colon/drug effects , Sulfonamides/pharmacology , Sulfonamides/administration & dosage , Purines , Azetidines/pharmacology , Azetidines/administration & dosage , Benzyl Compounds/pharmacology , Benzyl Compounds/administration & dosage , Piperidines/pharmacology , Piperidines/administration & dosage , Pyrimidines/pharmacology , Pyrimidines/administration & dosage , Drug Delivery Systems/methods , Oxadiazoles/pharmacology , Oxadiazoles/administration & dosage , Sphingosine-1-Phosphate Receptors/metabolism , Sphingosine-1-Phosphate Receptors/antagonists & inhibitors , Pyrroles/pharmacology , Pyrroles/administration & dosage , Indans/pharmacology , Indans/administration & dosage , Pyridines , TriazolesABSTRACT
Background: Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR1. In this first-in-human study, icanbelimod was investigated in healthy men in Australia. Methods: Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort. Results: Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (Tmax 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions. Conclusion: Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts. Clinical trial registration: ClinicalTrials.gov, identifier NCT02280434.b.
Subject(s)
Healthy Volunteers , Sphingosine 1 Phosphate Receptor Modulators , Humans , Male , Adult , Australia , Double-Blind Method , Young Adult , Sphingosine 1 Phosphate Receptor Modulators/pharmacokinetics , Sphingosine 1 Phosphate Receptor Modulators/adverse effects , Sphingosine 1 Phosphate Receptor Modulators/administration & dosage , Middle Aged , Sphingosine-1-Phosphate Receptors , Lymphocyte Count , AdolescentABSTRACT
BACKGROUND: Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), continues to challenge treatment paradigms. Advancements in therapeutic options have been have been driven by Phase 2 and 3 clinical trials of new drug classes, particularly sphingosine-1-phosphate (S1P) modulators and interleukin-23 (IL-23) inhibitors. METHODS: This review synthesizes findings from Phase 2 and 3 clinical trials conducted up to early 2024, focusing on the impact of S1P modulators and IL-23 inhibitors on IBD management. Drugs such as ozanimod, etrasimod, risankizumab, mirikizumab, guselkumab, and brasikumab were evaluated for their efficacy and safety profiles. RESULTS: S1P modulators, such as ozanimod and etrasimod, effectively regulate immune cell trafficking to reduce inflammation and several trials highlight their clinical effectiveness in both inducing and maintaining remission in IBD, highlighting its long-term safety and sustained therapeutic effects. Additionally, IL-23 inhibitors including risankizumab, mirikizumab, and guselkumab, which disrupt key inflammatory cytokine pathways, have already shown significant effectiveness in inducing and maintaining remission in both CD and UC, with favorable safety profiles across multiple studies, suggesting their potential as critical components in managing IBD. CONCLUSIONS: The clinical trials indicate that both S1P modulators and IL-23 inhibitors offer promising therapeutic benefits and maintain strong safety profiles, positioning them as potential cornerstone treatments for IBD. Despite these advancements, further exploration into long-term safety and the development of personalized treatment strategies is essential for maximizing clinical outcomes.
Subject(s)
Clinical Trials, Phase II as Topic , Interleukin-23 , Humans , Interleukin-23/antagonists & inhibitors , Clinical Trials, Phase III as Topic , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Gastrointestinal Agents/therapeutic use , Gastrointestinal Agents/pharmacologyABSTRACT
BACKGROUND AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. METHODS: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. RESULTS: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). DISCUSSION: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.
Subject(s)
Leukoencephalopathy, Progressive Multifocal , Natalizumab , Sphingosine 1 Phosphate Receptor Modulators , Humans , Leukoencephalopathy, Progressive Multifocal/chemically induced , Natalizumab/adverse effects , Male , Middle Aged , Female , Adult , Retrospective Studies , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Sphingosine 1 Phosphate Receptor Modulators/adverse effects , Multiple Sclerosis/drug therapy , Immunologic Factors/adverse effects , Immunologic Factors/pharmacology , Immunologic Factors/administration & dosage , Cohort Studies , Aged , Immune Reconstitution Inflammatory Syndrome/chemically inducedABSTRACT
Background: Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients. Methods: Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery. Results: SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod's protective effects. Conclusion: Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.
Subject(s)
Azetidines , Benzyl Compounds , Multiple Sclerosis, Chronic Progressive , Synapses , T-Lymphocytes , Humans , Animals , Mice , Female , Multiple Sclerosis, Chronic Progressive/immunology , Multiple Sclerosis, Chronic Progressive/drug therapy , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/drug effects , Azetidines/pharmacology , Azetidines/therapeutic use , Benzyl Compounds/pharmacology , Benzyl Compounds/therapeutic use , Male , Adult , Synapses/metabolism , Middle Aged , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Mice, Inbred C57BL , Sphingosine-1-Phosphate Receptors/metabolism , Synaptic Transmission/drug effects , Neurons/metabolism , Neurons/pathologyABSTRACT
OBJECTIVES: This study aimed to evaluate whether switching disease-modifying therapies (DMTs) from sphingosine-1 phosphate (S1P) receptor modulators to either natalizumab (NTZ) or dimethyl fumarate (DMF) could restore the effectiveness of SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis (MS). METHODS: This study included 9 controls and 33 patients with MS: 7 patients treated with DMF, 7 patients treated with NTZ, 9 patients treated with S1P receptor modulators, and 10 patients who had switched DMTs from S1P receptor modulators to DMF or NTZ by the second vaccine dose. The patients who had switched DMTs were classified into two groups, based on whether their lymphocyte counts were above or below 1000/µL at the time of vaccination. In addition, relapses within 6 months after switching DMTs were also evaluated in these patients. Six months after the second dose of the vaccination, anti-SARS-CoV-2 spike antibodies were evaluated in all participants, and spike specific CD4+ T cells were also assessed in patients who had switched DMTs from S1P receptor modulators. RESULTS: Patients treated with S1P receptor modulators had lower levels of anti-SARS-CoV-2 spike antibodies than the controls and patients treated with DMF and NTZ. On the other hand, in patients who had switched DMTs from S1P receptor modulators, a recovery of lymphocyte counts above 1000/µL resulted in restored humoral and cellular immune responses to the vaccination. There were no neurological relapses in patients who had switched DMTs from S1P receptor modulators to NTZ. CONCLUSION: SARS-CoV-2 mRNA vaccination is expected to be effective in patients whose lymphocyte counts have recovered due to switching DMTs from S1P receptor modulators. Switching DMTs from S1P receptor modulators to NTZ before vaccination may be beneficial in achieving efficacy for SARS-CoV-2 mRNA vaccination, with a reduced risk of relapse.
Subject(s)
COVID-19 , Dimethyl Fumarate , Multiple Sclerosis , Natalizumab , SARS-CoV-2 , Humans , Female , Dimethyl Fumarate/therapeutic use , Male , Adult , Natalizumab/therapeutic use , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/drug therapy , COVID-19/prevention & control , COVID-19/immunology , SARS-CoV-2/immunology , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Immunosuppressive Agents/therapeutic use , Vaccination/methods , Drug Substitution , Antibodies, Viral/bloodABSTRACT
Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases. Recent pivotal phase 3 trials involving treatments like interleukin-23-, sphingosin-1-phosphate- and Janus kinase inhibitors have demonstrated notable effectiveness. However, they have also unveiled significant side effects such as herpes zoster, lymphopenia and bradycardia. The introduction of novel treatments raises valid concerns necessitating increased collaboration with diverse medical specialities to address potentially severe side effects, and this is vital for enhancing the future care of individuals with inflammatory bowel diseases, as argued in this review.
Subject(s)
Biological Products , Colitis, Ulcerative , Crohn Disease , Humans , Crohn Disease/drug therapy , Colitis, Ulcerative/drug therapy , Biological Products/therapeutic use , Biological Products/adverse effects , Janus Kinase Inhibitors/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effectsABSTRACT
Osteoporosis is the most common bone disorder, in which an imbalance between osteoclastic bone resorption and osteoblastic bone formation disrupts bone homeostasis. Osteoporosis management using anti-osteoclastic agents is a promising strategy; however, this remains an unmet need. Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are essential for maintaining bone homeostasis. Here, we identified that Siponimod, a Food and Drug Administration-approved S1PR antagonist for the treatment of multiple sclerosis, shows promising therapeutic effects against osteoporosis by inhibiting osteoclast formation and function. We found that Siponimod inhibited osteoclast formation in a dose-dependent manner without causing cytotoxicity. Podosome belt staining and bone resorption assays indicated that Siponimod treatment impaired osteoclast function. Western blot and qPCR assays demonstrated that Siponimod suppressed the expression of osteoclast-specific markers, including C-Fos, Nftac1, and Ctsk. Mechanistically, we validated that Siponimod downregulated receptor activator of nuclear factor kappa B ligand (RANKL)-induced Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways during osteoclastogenesis. Moreover, in a preclinical mouse model, Siponimod prevented ovariectomy-induced bone loss by suppressing osteoclast activity in vivo. Collectively, these results suggest that Siponimod could serve as an alternative therapeutic agent for the treatment of osteoporosis.
Subject(s)
Azetidines , Benzyl Compounds , Drug Repositioning , Multiple Sclerosis , Osteoclasts , Osteoporosis , Animals , Mice , Osteoporosis/drug therapy , Osteoporosis/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , Benzyl Compounds/pharmacology , Benzyl Compounds/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , Multiple Sclerosis/drug therapy , Female , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Osteogenesis/drug effects , NF-kappa B/metabolism , Mice, Inbred C57BL , RAW 264.7 Cells , Bone Resorption/drug therapy , Signal Transduction/drug effects , RANK Ligand/metabolism , HumansSubject(s)
Multiple Sclerosis , Sphingosine 1 Phosphate Receptor Modulators , Adult , Female , Humans , Male , Middle Aged , Fingolimod Hydrochloride/adverse effects , Fingolimod Hydrochloride/therapeutic use , Multiple Sclerosis/drug therapy , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Sphingosine 1 Phosphate Receptor Modulators/pharmacologyABSTRACT
BACKGROUND: Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes. METHODS: We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs. RESULTS: At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression. CONCLUSIONS: Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes.
Subject(s)
Azetidines , Benzyl Compounds , Lymphocyte Subsets , Multiple Sclerosis, Chronic Progressive , Humans , Female , Male , Adult , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Chronic Progressive/immunology , Multiple Sclerosis, Chronic Progressive/blood , Azetidines/pharmacology , Azetidines/administration & dosage , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Middle Aged , Benzyl Compounds/pharmacology , Benzyl Compounds/administration & dosage , Retrospective Studies , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Follow-Up Studies , Treatment OutcomeABSTRACT
Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators are small molecule drugs (SMDs) approved for IBD treatment. Their use in clinical practice might be limited due to cardiovascular concerns. We aimed to provide guidance on risk assessment, monitoring, and management strategies, aiming to minimize potential cardiovascular risks of SMDs and to facilitate an adequate shared decision-making. A systematic literature search was conducted, and proposed statements were prepared. A virtual consensus meeting was held, in which eleven IBD physicians and two cardiovascular specialists from ten countries attended. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75 % of participants voting as 'agree' with each statement. Consensus was reached for eighteen statements. Available evidence does not show a higher risk of cardiovascular events with JAK inhibitors in the overall IBD population, although it might be increased in patients with an unfavorable cardiovascular profile. S1P receptor modulators may be associated with a risk of bradycardia, atrioventricular blocks, and hypertension. Cardiovascular risk stratification should be done before initiation of SMDs. Although the risk of cardiovascular events in patients with IBD on SMDs appears to be low overall, caution should still be taken in certain scenarios.
Subject(s)
Cardiovascular Diseases , Consensus , Delphi Technique , Inflammatory Bowel Diseases , Janus Kinase Inhibitors , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/complications , Cardiovascular Diseases/prevention & control , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Risk Assessment , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/adverse effectsABSTRACT
BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. METHODS: Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. RESULTS: On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. CONCLUSIONS: Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.
Subject(s)
COVID-19 Vaccines , COVID-19 , Multiple Sclerosis , Humans , COVID-19/prevention & control , COVID-19/immunology , Male , Female , Middle Aged , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Adult , COVID-19 Vaccines/therapeutic use , Retrospective Studies , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Treatment Outcome , Vaccination , Immunosuppressive Agents/therapeutic useABSTRACT
INTRODUCTION: Despite the growing number of highly efficacious biologics and chemical drugs for ulcerative colitis (UC), steroid-free disease control is still difficult to achieve in subgroups of patients due to refractoriness, adverse events, primary or secondary failure. New treatments are therefore still required in order to optimize clinical management of patients with UC. AREAS COVERED: The efficacy and safety of both currently available and newly developed small molecules have been summarized. The PubMed database and clinicaltrials.gov were considered in order to search for phase 2b and 3 trials on new chemical drugs for UC. The study drugs reviewed included Janus kinases (JAK) and sphingosine-1-phosphate receptor (S1Pr) inhibitors, α4 integrin antagonist, and micro-RNA-124 upregulators. EXPERT OPINION: Rapidity of onset, low immunogenicity, and safety are the main characteristics of small molecules currently available or under evaluation for treatment patients with UC. Among the currently available chemical drugs, the selective JAK and the S1Pr inhibitors are characterized by a good safety profile combined with the ability to induce clinical remission in UC. A relatively low frequency of endoscopic improvement and healing currently appears associated with their use, being higher in UC patients treated with S1Pr inhibitor Etrasimod. Overall, additional new safe and effective drugs are still required in order to optimize disease control in a larger majority of UC patients.
Subject(s)
Colitis, Ulcerative , Gastrointestinal Agents , Humans , Colitis, Ulcerative/drug therapy , Gastrointestinal Agents/therapeutic use , Gastrointestinal Agents/pharmacology , Gastrointestinal Agents/adverse effects , Drug Development , Animals , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/pharmacology , Sphingosine-1-Phosphate Receptors/antagonists & inhibitors , Sphingosine-1-Phosphate Receptors/metabolism , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Clinical Trials, Phase III as TopicABSTRACT
PURPOSE: FTY720 is an agonist of the Sphingosine-1-phosphate (S1P) receptor 1, 3, 4, and 5 and a functional antagonist of the S1P1 receptor; it can inhibit the activation of mTOR/NF-κB and has therapeutic potential in inflammatory disease. This study was designed to determine the role of the inflammatory process in diabetic retinopathy and investigate the effect of FTY720 on high glucose (HG)-induced rat retinal Müller cells (rMC-1 cells). METHODS: In the present study, the role of FTY720 in inhibiting inflammation and its underlying mechanism were investigated. rMC-1 cells were treated without or with HG, FTY720, CQ, or RAP. Cell viability was examined by CCK-8 assay; cell activation was assessed by western blot analysis and IF staining; and cell migration was evaluated by a scratch wound healing assay. The expression of inflammation-associated proteins and autophagy-related proteins was evaluated by transmission electron microscopy, AO staining, MDC-labeled autophagic vacuoles, western blot analysis and ELISA. RESULTS: Western blot analysis and IF staining showed that the level of the rMC-1 cell marker GFAP was decreased, while GS was increased in FTY720 groups compared to that in the HG group. The healing assay results showed that compared with HG treatment, FTY720 treatment significantly reduced cell migration. Western blot analysis, ELISA and IF staining showed that compared with HG, FTY720 reduced proinflammatory proteins by inhibiting the mechanistic target of the mTOR/NF-κB signaling pathway and regulating autophagy. CONCLUSIONS: This study suggests that in an HG-induced rMC-1 cell model, FTY720 significantly inhibited the production of inflammatory cytokines by inhibiting mTOR/NF-κB signaling and regulating autophagy. These findings were associated with a decrease in rMC-1 cell injury, suggesting that FTY720 or related compounds may be valuable modulators of HG-induced retinal injury.
Subject(s)
Autophagy , Blotting, Western , Cell Movement , Cell Survival , Diabetic Retinopathy , Ependymoglial Cells , Fingolimod Hydrochloride , NF-kappa B , Signal Transduction , TOR Serine-Threonine Kinases , Fingolimod Hydrochloride/pharmacology , Animals , Rats , Ependymoglial Cells/drug effects , Ependymoglial Cells/metabolism , Ependymoglial Cells/pathology , TOR Serine-Threonine Kinases/metabolism , NF-kappa B/metabolism , Autophagy/drug effects , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/drug therapy , Cell Survival/drug effects , Cell Movement/drug effects , Enzyme-Linked Immunosorbent Assay , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Cells, Cultured , Immunosuppressive Agents/pharmacology , Microscopy, Electron, Transmission , Disease ProgressionABSTRACT
BACKGROUND AND AIMS: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. METHODS: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. RESULTS: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all pâ <â 0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. CONCLUSIONS: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52. Clinicaltrials.gov: NCT03945188; NCT03996369.
Subject(s)
Colitis, Ulcerative , Proctitis , Humans , Proctitis/drug therapy , Proctitis/etiology , Male , Female , Adult , Colitis, Ulcerative/drug therapy , Middle Aged , Double-Blind Method , Treatment Outcome , Severity of Illness Index , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Remission Induction/methodsABSTRACT
BACKGROUND: Ozanimod showed efficacy and safety in the phase 2 STEPSTONE study conducted in patients with moderately to severely active Crohn's disease. AIMS: This analysis assessed the effects of ozanimod on circulating lymphocytes in Crohn's disease. METHODS: Patients received ozanimod 0.92 mg for 12 weeks. Lymphocyte subtypes were evaluated using multicolor flow analysis on blood samples collected before treatment and on Week 12. Absolute lymphocyte count changes were analyzed by Wilcoxon signed rank tests. Disease activity changes and efficacy outcomes were evaluated at Week 12, and associations with lymphocyte subtype levels were assessed using Spearman's correlation and logistic regression. RESULTS: Reductions in median total T, Th, and cytotoxic T cells occurred at Week 12 (45.4%-76.8%), with reductions in most subtypes of 47.5% to 91.3% (P < 0.001). CD8+ terminally differentiated effector memory cells were largely unaffected (median change, - 19%; P = 0.44). Reductions in median total B cells occurred at Week 12 (76.7%), with reductions in subtypes of 71.4% to 81.7% (P < 0.001). Natural killer and monocyte cell counts were unchanged. Greater baseline levels and changes in nonswitched memory B cells were significantly associated with clinical, endoscopic, and histologic efficacy (P < 0.05, all comparisons). CONCLUSIONS: Ozanimod reduced circulating levels of all B-cell and most T-cell subsets but not monocytes or natural killer cells. Key subsets relevant to immune surveillance were not reduced, supporting the low risk of infection and malignancy with ozanimod in chronic inflammatory diseases. Levels of nonswitched memory B cells were associated with efficacy, providing a potential marker for ozanimod response. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02531113, EudraCT: 2015-002025-19.